ROP, a leading cause of blindness in children, afflicts ~16,000 premature infants yearly in the US1. ROP incidence is increasing because of more in vitro fertilization resulting in more multiple births with lower birth weight. Also, increasingly low gestational age infants survive. Oxygen is supplemented at higher levels with more ROP. Current ROP treatments (laser photocoagulation and anti-VEGF therapy) are not always effective, and long-term anti-VEGF therapy may potentially impair brain and organ development. We need to find ways to treat early to prevent phase I ROP, and thus prevent neovascularization. Hyperglycemia and associated dyslipidemia, commonly see in preterm infants and associated with ROP development, may contribute to vessel loss in phase I ROP. We must understand the mechanism to develop safe and effective treatment for early ROP to prevent late phase II neovascularization. We preliminarily found that fibroblast growth factor 21 (FGF21), a significant glucose/lipid metabolic modulator, prevents retinal vascular delay in a mouse model of phase I ROP. Therefore, we propose that In dyslipidemia/hyperglycemia-exacerbated phase I ROP, FGF21 improves glucose/lipid metabolism and vessel development. In the mouse model of ROP with neonatal metabolic dysfunction (NMD-ROP), we will examine if 1) FGF21 improves retinal vascular development; 2) FGF21 effect on lipid/glucose metabolism; 3) does FGF21 promote normal vascularization by regulating glial cell metabolism and angiogenic factors. This study will determine 1) the role of FGF21 in a novel mouse model of hyperglycemia-exacerbated phase I ROP; 2) the metabolic impact of FGF21 on retinal lipid and glucose use; 3) the role of retinal glial cell metabolism in supporting retinal vessel growth. FGF21 may prevent and treat ROP at an early stage.